The overall goal of this proposal is to delineate the mechanisms underlying the formation of pancreatic cancer. Pancreatic ductal adenocarcinoma (PDA) is a lethal tumor unreceptive to extant treatment. While significant efforts have been undertaken to define the molecular mechanisms that guide the formation of this aggressive tumor, important aspects of the progression from normal pancreas exocrine cells to neoplastic tissue remain unknown. Our recent results have suggested that the canonical Wnt signaling pathway plays a critical role in distinguishing between acinar cell regeneration in normal cells versus pathological acinar- ductal metaplasia (ADM) followed by pancreatic intraepithelial neoplasia (PanIN)/PDA formation in the context of Kras mutations. The objectives of this proposal are to define the roles of the Wnt signaling pathway during acinar cell regeneration and in the formation of pathological ADM, PanIN, and PDA. Preliminary results suggest interactions between Wnt signaling and Kras signaling, a pathway known to promote PanIN and PDA formation in mouse and human. To accomplish our goals, we propose to use sophisticated transgenic mouse model strategies to unravel the role of Wnt signaling in normal acinar regeneration as well as cancer formation and progression. The transgenic mouse models will be used to activate and inactivate Wnt signaling in the context of a regenerating pancreas. Mouse models will also be employed to analyze the contribution of Wnt signaling to the progression of PDA. In summary, this proposal aims to understand how interactions between Kras and Wnt signaling affect the formation of early tumor progenitors and whether elimination of Wnt signaling in PanIN and PDA could eventually be exploited as a novel therapeutic target to block tumor progression. PUBLIC HEALTH RELEVANCE: This proposal aims to compare the role of Wnt signaling, an embryonic signaling pathway, during normal pancreas regeneration to the pathological processes that result in the formation of acinar-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN), and finally pancreatic adenocarcinoma (PDA). Understanding the mechanisms that regulate the switch between normal pancreas regeneration upon injury and the pathological formation of cancer progenitors is important as it may reveal novel ways to either identify early lesions before they turn into cancer or to develop novel strategies to combat this lethal disease.